MEK Inhibitor AZD6244 With or Without Temsirolimus in Treating Patients With Metastatic, Recurrent, or Locally Advanced Soft Tissue Sarcoma That Cannot Be Removed By Surgery

• Response by Choi criteria [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
• Toxicity, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]

• Response by Choi criteria [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]

This randomized phase II trial is studying how well giving MEK inhibitor AZD6244 together with or without temsirolimus works in treating patients with metastatic, recurrent, or locally advanced soft tissue sarcoma that cannot be removed by surgery. MEK inhibitor AZD6244 and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving MEK inhibitor AZD6244 together with temsirolimus is more effective than giving MEK inhibitor AZD6244 alone

PRIMARY OBJECTIVES:

I. Compare the progression-free survival of the MEK inhibitor, AZD6244 alone, and the combination of AZD6244 and a mammalian target of rapamycin inhibitor (mTORi), temsirolimus (CCI-779) in patients with recurrent metastatic or recurrent locally unresectable soft-tissue sarcomas.

SECONDARY OBJECTIVES:

I. Determine the rates of apoptosis, autophagy, and proliferation with AZD6244 alone, and in combination with temsirolimus by immunohistochemistry in tumor and surrogate skin tissue biopsies. (exploratory) II. Assess the activation status of protein kinase B (Akt), 5E-BP1, eukaryotic translation initiation factor 4 gamma, 1 (eIF-4G), and ribosomal protein S6 kinase (S6K) in tumor biopsy samples and surrogate skin tissue biopsy samples.(exploratory) III. Assess inhibition of activated mitogen-activated protein kinase 1/2 (ERK1/2) in stimulated peripheral blood mononuclear cells. (exploratory) IV. Assess response by Choi criteria. V. Compare the response rate and 4-month progression-free survival (PFS) rate in patients treated with these regimens.

VI. Compare the response rate, 4-month PFS rate and toxicity of AZD6244 alone and in combination with temsirolimus.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28 and temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22.

ARM II: Patients receive MEK inhibitor AZD6244 as in arm I. Patients who experience disease progression may cross over to arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for 30 days.

• Recurrent Adult Soft Tissue Sarcoma
• Stage III Adult Soft Tissue Sarcoma
• Stage IV Adult Soft Tissue Sarcoma

• Drug: selumetinib
  Given orally
  Other Names:

  • ARRY-142886
  • AZD6244
• Drug: temsirolimus
  Given IV
  Other Names:

  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm I (MEK inhibitor AZD6244 and temsirolimus)
  Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28 and temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22.
  Interventions:

  • Drug: selumetinib
  • Drug: temsirolimus
  • Other: laboratory biomarker analysis
• Experimental: Arm II (MEK inhibitor AZD6244)
  Patients receive MEK inhibitor AZD6244 as in arm I. Patients who experience disease progression may cross over to arm I.
  Interventions:

  • Drug: selumetinib
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Histologically confirmed soft-tissue sarcoma at original diagnosis meeting 1 of the following criteria:

  • Metastatic (de novo or recurrent) disease
  • Locally advanced unresectable disease
  • Gastrointestinal stromal tumor (GIST) subtype allowed
  • No pediatric-type sarcomas (e.g., Ewing's or primitive neuroectodermal tumor, rhabdomyosarcoma, and desmoplastic small round cell tumor)
• Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral computed tomography (CT) scan
• Patients with CNS tumors must have been on a stable or decreasing dose of dexamethasone for more than 7 days
• No known brain metastases
• ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• Life expectancy > 12 weeks
• ANC ≥ 1,000/μL
• Platelet count ≥ 100,000/μL (transfusion independent)
• Hemoglobin ≥ 8.0 mg/dL (may receive red blood cell transfusions)
• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 45 mL/min
• Bilirubin (sum of conjugated plus unconjugated) ≤ 1.5 times ULN
• ALT ≤ 5 times ULN
• Serum albumin ≥ 2 g/dL
• Fertile patients must use effective contraception during and for 4 weeks (women) or for 16 weeks (men) after completion of last dose of treatment
• Negative pregnancy test
• Not pregnant or nursing
• No evidence of dyspnea at rest and/or exercise intolerance
• Pulse oximetry > 94% if there is clinical indication for determination
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition toMEK inhibitor AZD6244
• No QTc interval > 450 msecs, other factors that increase the risk of QT prolongation, or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome)
• Able to swallow capsules
• No refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease),or significant bowel resection that would preclude adequate absorption

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Psychiatric illness and/or social situations that would limit compliance with study requirements
• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

• None of the following:

  • Cardiac history of uncontrolled hypertension
  • NYHA class II-IV cardiac disease
  • Prior or current cardiomyopathy
  • Baseline LVEF < 50%
  • Ongoing atrial fibrillation
  • Recent myocardial infarction
  • Unstable ischemic heart disease
• No concurrent strong CYP1A2 or CYP3A4 inducers and/or inhibitors
• Up to 2 prior cytotoxic chemotherapeutic regimens (single-agent or combination of chemotherapies) for metastatic or recurrent disease allowed
• At least 1 week since prior growth factors that support platelet or white cell number or function
• At least 3 weeks since prior chemotherapy or radiotherapy (6 weeks for mitomycin C and nitrosoureas)
• No prior MEK inhibitor(s)
• No prior mTOR inhibitor for recurrent soft-tissue sarcoma
• No concurrent growth factor(s) that support platelet or white cell count or function within the past 7 days
• No other concurrent investigational drug
• No other concurrent anticancer agents including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
• No concurrent combination antiretroviral therapy for HIV-positive patients